Expression of androgen receptor coactivators in normal and cancer prostate tissues and cultured cell lines

Mestayer, Chidi; Blanchere, Marie; Jaubert, Françis; Dufour, B; Mowszowicz, Irène

doi:10.1002/pros.10229

Cited by 51 publications

(45 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…We have found that several different coactivators are coexpressed with AR in the luminal epithelial cells of the prostate, where the majority of cancers arise. Although studies measuring expression of individual coactivators in prostate cancer have shown few convincing changes in levels correlating with progression to hormone independence, this could be a consequence of small subsets of cofactors being investigated (Fujimoto et al 2001, Gnanapragasam et al 2001, Mestayer et al 2003. Over 200 potential cofactors have been identified so far, many of which appear to function as part of large, multiprotein complexes, so if alterations in coactivators do contribute to hormone resistance, it may well be subtle changes in ratios between various types of cofactor.…”

Section: Discussionmentioning

confidence: 99%

Mechanisms of androgen receptor signalling via steroid receptor coactivator-1 in prostate.

Powell

Christiaens²,

Voulgaraki³

et al. 2004

Endocr Relat Cancer

View full text Add to dashboard Cite

The androgen receptor (AR) is a member of the nuclear receptor superfamily. These ligand-activated transcription factors usually contain two activation functions, a ligand-independent activation function 1(AF1) in the divergent N-terminal domain and a ligand-dependent AF2 in the more conserved Cterminal ligand-binding domain. To promote transcription from target promoters, DNA-bound nuclear receptors recruit coactivator proteins that promote transcription by modifying histones within nucleosomes, resulting in altered topology of chromatin to allow access of the basal transcriptional machinery, or stabilising the pre-initiation complex. It is well known that most coactivators interact with AF2 of many nuclear receptors via conserved, helical LxxLL motifs (where L is leucine and x is any amino acid). The AF2 of the AR is very weak, but we were able to demonstrate that its intrinsic liganddependent activity is potentiated by steroid receptor coactivator-1 (SRC1) and that this region interacts with coactivators via LxxLL motifs. However, a mutant SRC1 coactivator with no functional LxxLL motifs was still able to potentiate AR activity. We found that SRC1 can also be recruited to (and increase activity of) AF1 of the AR via a conserved, glutamine-rich region. Point mutations within this region abolish SRC1 interaction with AF1 and also abolish or severely impair its ability to potentiate AR activity on all promoters tested. Thus the AR interacts with SRC1 via two different regions and the AF1 interaction is functionally the more important, although the contribution of the two interactions varies in a promoter-dependent fashion. SRC1 then potentiates receptor activity via recruitment of CBP/p300, a histone acetyltranferase. This is important in the context of prostate cancer as SRC1 and other coactivators including CBP are coexpressed with AR in the luminal epithelial cells of the prostate, where over 90% of prostate tumours arise. There is a need for effective second-line prostate cancer therapy aimed at blocking the AR pathway when anti-androgen therapy has failed. Since there is growing evidence that nuclear receptor cofactors may be implicated in the progression of hormone-dependent tumours to hormoneindependent states, novel targets could include the interaction of AR with coactivator proteins. We suggest that the N-terminal interaction would be a more specific and effective target in the case of prostate cancer than the LxxLL/AF2 interaction.

show abstract

Section: Discussionmentioning

confidence: 99%

Mechanisms of androgen receptor signalling via steroid receptor coactivator-1 in prostate.

Powell

Christiaens²,

Voulgaraki³

et al. 2004

Endocr Relat Cancer

View full text Add to dashboard Cite

show abstract

“…At the mRNA level, however, decreased or unaltered SRC-1 levels in malignant versus benign prostate have been reported (Fujimoto et al, 2001;Linja et al, 2004;Maki et al, 2006). Studies on expression of ARA70 in prostate cancer are equally contradictory with the co-activator being found to be both upregulated at the protein level (Hu et al, 2004) and downregulated at the RNA level (Li et al, 2002) in tumours versus benign tissue, whereas others have found no change in mRNA levels (Mestayer et al, 2003). In light of the current study, a possible explanation of the conflicting results of such studies could be differences in hormonal treatment regimes in the patients.…”

Section: Discussionmentioning

confidence: 99%

Mechanisms of androgen receptor activation in advanced prostate cancer: differential co-activator recruitment and gene expression

2007

View full text Add to dashboard Cite

Prostate tumour growth depends on androgens; hence treatment includes androgen ablation and anti-androgens. Eventually tumours progress and in approximately 30% of patients this is associated with mutation of the androgen receptor. Several receptor variants associated with advanced disease show promiscuous activation by other hormones and anti-androgens. Such loss of specificity could promote receptor activation, hence tumour growth, in the absence of conventional ligands, explaining therapy failure. We aimed to elucidate mechanisms by which alternative ligands promote receptor activation. The three most commonly identified variants in tumours (with amino-acid substitutions H874Y, T877A and T877S) and wild-type receptor showed differences in co-activator recruitment dependent upon ligand and the interaction motif utilized. Co-expression and knockdown of co-activators that bind via leucine or phenylalanine motifs, combined with chromatin immunoprecipitation and quantitative PCR, revealed these preferences extend to co-activator recruitment in vivo and affect receptor activity at the transcriptional level, with subsequent effects on target gene regulation. The findings suggest that mutant receptors, activated by alternative ligands, drive growth via different mechanisms to androgenactivated wild-type receptor. Tumours may hence behave differently dependent upon any androgen receptor mutation present and what ligand is driving growth, as distinct subsets of genes may be regulated.

show abstract

“…In the non-pathological state, the interplay of AR with its coregulators within the nucleus is tightly controlled and is essential for the regulation of genomic, ligand-activated functions (Mestayer et al 2003, Xu et al 2009a). In the malignant and castration-resistant states, deregulation of this interplay is common and frequently manifested by increased expression and activity of AR coactivators with a concomitant inhibition or loss of AR corepressors 23:12 (Supplementary Table 3).…”

Section: Ar Coregulator Alterations In Crpcmentioning

confidence: 99%

“…What are the therapeutic consequences of the co-existence of multiple forms of persistent, aberrant AR signaling in (Mestayer et al 2003, Xu et al 2009a). Can we push AR towards its 'normal' function by shaping, both qualitatively and quantitatively, the AR interactome?…”

Section: Concluding Remarks and Future Directionsmentioning

confidence: 99%

Androgen receptor signaling in castration-resistant prostate cancer: a lesson in persistence

Coutinho¹,

Day²,

Tilley³

et al. 2016

Endocrine-Related Cancer

150

122

View full text Add to dashboard Cite

The androgen receptor (AR) signaling axis drives all stages of prostate cancer, including the lethal, drug-resistant form of the disease termed castration-resistant prostate cancer (CRPC), which arises after failure of androgen deprivation therapy (ADT). Persistent AR activity in spite of ADT and the second-generation AR-targeting agents enzalutamide and abiraterone is achieved in many cases by direct alterations to the AR signaling axis. Herein, we provide a detailed description of how such alterations contribute to the development and progression of CRPC. Aspects of this broad and ever-evolving field specifically addressed in this review include: the etiology and significance of increased AR expression; the frequency and role of gain-of-function mutations in the AR gene; the function of constitutively active, truncated forms of the AR termed AR variants and the clinical relevance of alterations to the activity and expression of AR coregulators. Additionally, we examine the novel therapeutic strategies to inhibit these classes of therapy resistance mechanisms, with an emphasis on emerging agents that act in a manner distinct from the current ligand-centric approaches. Throughout, we discuss how the central role of AR in prostate cancer and the constant evolution of the AR signaling axis during disease progression represent archetypes of two key concepts in oncology, oncogene addiction and therapy-mediated selection pressure.

show abstract

Expression of androgen receptor coactivators in normal and cancer prostate tissues and cultured cell lines

Cited by 51 publications

References 37 publications

Mechanisms of androgen receptor signalling via steroid receptor coactivator-1 in prostate.

Mechanisms of androgen receptor signalling via steroid receptor coactivator-1 in prostate.

Mechanisms of androgen receptor activation in advanced prostate cancer: differential co-activator recruitment and gene expression

Androgen receptor signaling in castration-resistant prostate cancer: a lesson in persistence

Contact Info

Product

Resources

About